Staphylococcus aureus is capable of causing a wide range of human diseases. It has become more problematic recently due to increasing resistance of the organism to antibiotic treatment. New methods of treatment are therefore urgently needed. The pathogenicity of this organism could be attributed to its ability to produce a large number of cell surface-associated and extracellular virulence factors. These virulence determinants are coordinately regulated by several unlinked global regulatory loci. Recently, we have identified a novel locus, mgr, which affects the production of several virulence factors in a pattern distinct from other systems reported to date. We have subsequently employed genetic and molecular methods to map and clone this global regulatory locus. Sequencing, gene-specific mutation and complementation confirmed that the mgr was a novel locus. Our data also suggest that mgrA is most likely the only gene in this locus that is required in the regulation. In this proposal, we propose to accomplish three specific aims: (i) to molecularly characterize the mgr locus by studying the transcriptional organization and analyzing the promoter region of the mgrA gene; (ii) to investigate the mechanism of target gene regulation by mgr and to identify additional target genes by micorarray technology; (iii) to study interaction with other global regulatory systems and control of mgrA gene expression. Various genetic, biochemical and molecular approaches will be employed to accomplish these aims. The successful completion of the studies outlined in this proposal will provide further insights into the mgr regulatory system. The new knowledge will undoubtedly contribute to our understanding of global regulatory mechanism in S. aureus, which will further provide a solid basis for the development of new treatments. [unreadable] [unreadable]